The present invention relates to novel sulphonamide derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use as potentiators of glutamate receptor function.
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmitter in the CNS, mediates the major excitatory pathway in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins and Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981) ; Monaghan, Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception.
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed xe2x80x9cionotropicxe2x80x9d. This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type of receptor is the G-protein or second messenger-linked xe2x80x9cmetabotropicxe2x80x9d excitatory amino acid receptor. This second type is coupled to multiple second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation of phospholipase D, increases or decreases in c-AMP formation, and changes in ion channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both types of receptors appear not only to mediate normal synaptic transmission along excitatory pathways, but also participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15, 41 (1990).
AMPA receptors are assembled from four protein sub-units known as GluR1 to GluR4, while kainic acid receptors are assembled from the sub-units GluR5 to GluR7, and KA-1 and KA-2. Wong and Mayer, Molecular Pharmacology 44: 505-510, 1993. It is not yet known how these sub-units are combined in the natural state. However, the structures of certain human variants of each sub-unit have been elucidated, and cell lines expressing individual sub-unit variants have been cloned and incorporated into test systems designed to identify compounds which bind to or interact with them, and hence which may modulate their function. Thus, European patent application, publication number EP-A2-0574257 discloses the human sub-unit variants GluR1B, GluR2B, GluR3A and GluR3B. European patent application, publication number EP-A1-0583917 discloses the human sub-unit variant GluR4B.
One distinctive property of AMPA and kainic acid receptors is their rapid deactivation and desensitization to glutamate. Yamada and Tang, The Journal of Neuroscience, September 1993, 13(9): 3904-3915 and Kathryn M. Partin, J. Neuroscience, Nov. 1, 1996, 16(21):6634-6647. The physiological implications of rapid desensitization, and deactivation if any, are unknown.
It is known that the rapid desensitization and deactivation of AMPA and/or kainic acid receptors to glutamate may be inhibited using certain compounds. This action of these compounds is often referred to in the alternative as xe2x80x9cpotentiationxe2x80x9d of the receptors. One such compound, which selectively potentiates AMPA receptor function, is cyclothiazide. Partin et al., Neuron. Vol. 11, 1069-1082, 1993. Compounds which potentiate AMPA receptors, like cyclothiazide, are often referred to as ampakines.
International Patent Application Publication Number WO 9625926 discloses a group of phenylthioalkylsulphonamides, S-oxides and homologs which are said to potentiate membrane currents induced by kainic acid and AMPA.
Ampakines have been shown to improve memory in a variety of animal tests. Staubli et al., Proc. Natl. Acad. Sci., Vol. 91, pp 777-781, 1994, Neurobiology, and Arai et al., The Journal of Pharmacology and Experimental Therapeutics, 278: 627-638, 1996.
It has now been found that cyclothiazide and certain novel sulphonamide derivatives potentiate agonist-induced excitability of human GluR4B receptor expressed in HEK 293 cells. Since cyclothiazide is known to potentiate glutamate receptor function in vivo, it is believed that this finding portends that the sulphonamide derivatives will also potentiate glutamate receptor function in vivo, and hence that the compounds will exhibit ampakine-like behavior.
Accordingly, the present invention provides a compound of formula I: 
in which:
A represents CR5(X1R6) or Cxe2x95x90NO(CH2)nR7;
R1 represents hydrogen, or together with R5 a bond;
R2 and R3 each independently represents hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring;
R4 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group;
R5 represents hydrogen, hydroxy, (1-4C)alkoxy, (1-4C)alkoxycarbonyl, or together with a substituent on R6 a bond, or together with R1 a bond;
X1 represents a bond, or when R1 represents hydrogen, NHCO;
R6 represents (3-8C)cycloalkyl or an unsubstituted or substituted aromatic or heteroaromatic group;
n is an integer of from 1 to 4; and
R7 is as defined for R6;
or a pharmaceutically acceptable salt thereof.
The present invention further provides compounds of the formula XVII: 
in which:
R2 and R3 each independently represents hydrogen or (1-4C)alkyl, or together with the carbon atom to which they are attached form a (3-6C)cycloalkyl ring;
R4 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group;and
R6 represents (3-8C)cycloalkyl or an unsubstituted or substituted aromatic or heteroaromatic group;
or a pharmaceutically acceptable salt thereof.
According to another aspect, the present invention provides a method of potentiating glutamate receptor function in a mammal requiring treatment, which comprises administering an effective amount of a compound of formula I or formula XVII, or a pharmaceutically acceptable salt thereof.
According to another aspect, the present invention provides the use of a compound of formula I or formula XVII, or a pharmaceutically acceptable salt thereof as defined hereinabove for the manufacture of a medicament for potentiating glutamate receptor function.
According to yet another aspect, the present invention provides the use of a compound of formula I or formula XVII or a pharmaceutically acceptable salt thereof as defined hereinabove for potentiating glutamate receptor function.
In this specification, the term xe2x80x9cpotentiating glutamate receptor functionxe2x80x9d refers to any increased responsiveness of glutamate receptors, for example AMPA receptors, to glutamate or an agonist, and includes but is not limited to inhibition of rapid desensitisation or deactivation of AMPA receptors to glutamate.
A wide variety of conditions may be treated or prevented by the compounds of formula I or formula XVII and their pharmaceutically acceptable salts through their action as potentiators of glutamate receptor function. Such conditions include those associated with glutamate hypofunction, such as psychiatric and neurological disorders, for example cognitive disorders; neuro-degenerative disorders such as Alzheimer""s disease; age-related dementias; age-induced memory impairment; movement disorders such as tardive dyskinesia, Hungtington""s chorea, myoclonus and Parkinson""s disease; sexual dysfunction; reversal of drug-induced states (such as cocaine, amphetamines, alcohol-induced states); depression; attention deficit disorder; attention deficit hyperactivity disorder; psychosis; cognitive deficits associated with psychosis; and drug-induced psychosis. The compounds of formula I or formula XVII may also be useful for improving memory (both short term and long term) and learning ability. The present invention provides the use of compounds of formula I or formula XVII for the treatment of each of these conditions.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as xe2x80x9cepimersxe2x80x9d. The terms xe2x80x9cracematexe2x80x9d, xe2x80x9cracemic mixturexe2x80x9d or xe2x80x9cracemic modificationxe2x80x9d refer to a mixture of equal parts of enantiomers.
The term xe2x80x9cenantiomeric enrichmentxe2x80x9d as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or xe2x80x9ceexe2x80x9d, which is found using the following equation:   ee  =                              E          1                -                  E          2                                      E          1                +                  E          2                      xc3x97    100  
wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I or of formula XVII can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc., 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. It is understood that all such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms xe2x80x9cRxe2x80x9d and xe2x80x9cSxe2x80x9d are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term xe2x80x9cRxe2x80x9d (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term xe2x80x9cSxe2x80x9d (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in xe2x80x9cNomenclature of Organic Compounds: Principles and Practicexe2x80x9d, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.
The designation  refers to a bond that protrudes forward out of the plane of the page.
The designations  refers to a bond that protrudes backward out of the plane of the page.
For compounds of formula I in which A represents CR5(X1R6), preferably the group R5 and the sulphonamide group are in a cis relationship as shown below. Such compounds are referred to hereinafter as the cis isomers. 
Mixtures of cis and trans isomers can be separated into the individual cis and trans isomers, which are included within the scope of the present invention, by one of ordinary skill in the art, using standard techniques and procedures such as reverse phase or normal phase high performance liquid chromatography or flash chromatography, with a suitable stationary phase and a suitable eluent. Examples of suitable stationary phases are silica gel, alumina, and the like. Examples of suitable eluents are ethyl acetate/hexane, ethyl acetate/toluene, methanol/dichloromethane, and the like.
It will be appreciated that when R5 together with R1 represents a bond, X1 must represent a bond, and when R1 represents hydrogen, X1 may alternatively represent a bond or NHCO. Thus, it is understood that compounds of the formula Ia or formula Ib: 
are included within the scope of formula I wherein the substituents are defined as hereinabove.
It will be appreciated that certain compounds of formula I or formula XVII possess an acidic or basic group, and may therefore form pharmaceutically acceptable salts with pharmaceutically acceptable bases or acids. Examples of pharmaceutically acceptable bases and acids include ammonia, alkali and alkaline earth metal hydroxides; inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, and phosphoric acid, as well as organic acids such as para-toluenesulfonic, methanesulfonic, oxalic, para-bromophenyl-sulfonic, carbonic, succinic, citric, benzoic, and acetic acid, and related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, ammonium, monohydrogenphosphate, dihydrogenphosphate meta-phosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebaculfate, uate, hippurate, butyne-1,4-dioate, hexane-1,6-diospate, beniumte, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex1-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, magnesium, tetramethylanunonium, potassium, trimethylammonium, sodium, methylammonium, calcium, and the like salts. It is understood that the above salts may form hydrates or exist in a substantially anhydrous form.
The term xe2x80x9ctreatingxe2x80x9d (or xe2x80x9ctreatxe2x80x9d) as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, or a resultant symptom.
As used herein, the term xe2x80x9caromatic groupxe2x80x9d means the same as aryl, and includes phenyl and a polycyclic aromatic carbocyclic ring such as naphthyl.
As used herein, the terms xe2x80x9cMexe2x80x9d, xe2x80x9cEtxe2x80x9d, xe2x80x9cPrxe2x80x9d, xe2x80x9ciPrxe2x80x9d, and xe2x80x9cBuxe2x80x9d refer to a methyl, ethyl, propyl, isopropyl and butyl group respectively.
The term xe2x80x9cheteroaromatic groupxe2x80x9d includes an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a bicyclic group consisting of a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or another 5-6 membered ring containing one to four atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaromatic groups are thienyl, furyl, oxazolyl, isoxazolyl, oxadiazoyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, quinolyl, indazole, and benzotriazole.
The term xe2x80x9csubstitutedxe2x80x9d as used in the term xe2x80x9csubstituted aromatic or heteroaromatic groupxe2x80x9d herein signifies that one or more (for example one or two) substituents may be present, said substituents being selected from atoms and groups which, when present in the compound of formula I or formula XVII, do not prevent the compound of formula I or formula XVII from functioning as a potentiator of glutamate receptor function.
Examples of substituents which may be present in a substituted aromatic or heteroaromatic group include halogen; amino; cyano; formyl; carboxy; nitro; (1-4C)alkyl; (2-4C)alkenyl; (2-4C)alkynyl; halo(1-4C)alkyl; cyano(1-4C)alkyl; amino(1-4C)alkyl; (1-4C)alkyl-NHSO2R17; (1-4C)alkyl-CO2R18; (1-4C)alkyl-CO2H; (1-4C)alkyl-CONR9R10; (3-8C)cycloalkyl; 2,5-dimethylpyrrolyl; wherein R17 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; R18 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, and groups of formula (L1)x-X2-(L1)y-R11 in which each of L1 and L2 independently represents (1-4C)alkylene, one of x and y is 0 and the other is 0 or 1, X2 represents a bond, O, S, NH, CO, CONH or NHCO, and R11 represents a furyl, thienyl, thiazolyl, pyridyl or phenyl group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl and (1-4C)haloalkyl.
The term (1-6C)alkyl includes (1-4C)alkyl. Particular values are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
The term (2-6C)alkenyl includes (3-6C)alkenyl and (2-4C)alkenyl. Particular values are vinyl and prop-2-enyl.
The term (2-6C)alkynyl includes (3-6C)alkynyl and (3-4C)alkynyl. A particular value is prop-2-ynyl.
The term (3-8C)cycloalkyl includes (3-6C)cycloalkyl. Particular values include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term halogen includes fluorine, chlorine, bromine and iodine.
The term halo(1-6C)alkyl includes fluoro(1-6C)alkyl, such as trifluoromethyl and 2,2,2-trifluoroethyl, and chloro(1-6C)alkyl such as chloromethyl.
The term (2-4C)alkylene includes ethylene, propylene and butylene. A preferred value is ethylene.
The term (1-4C)alkylphenyl includes the following: 
The term thienyl includes thien-2-yl and thien-3-yl.
The term furyl includes fur-2-yl and fur-3-yl.
The term oxazolyl includes oxazol-2-yl, oxazol-4-yl and oxazol-5-yl.
The term isoxazolyl includes isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl.
The term oxadiazolyl includes [1,2,4]oxadiazol-3-yl and [1,2,4]oxadiazol-5-yl.
The term pyrazolyl includes pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl.
The term thiazolyl includes thiazol-2-yl, thiazol-4-yl and thiazol-5-yl.
The term thiadiazolyl includes [1,2,4]thiadiazol-3-yl, and [1,2,4]thiadiazol-5-yl.
The term isothiazolyl includes isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl.
The term imidazolyl includes imidazol-2-yl, imidazolyl-4-yl and imidazolyl-5-yl.
The term triazolyl includes [1,2,4]triazol-3-yl and [1,2,4]triazol-5-yl.
The term tetrazolyl includes tetrazol-5-yl.
The term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl.
The term pyridazinyl includes pyridazin-3-yl, pyridazin-4-yl, pyridazin-5-yl and pyridazin-6-yl.
The term pyrimidyl includes pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl.
The term benzofuryl includes benzofur-2-yl and benzofur-3-yl.
The term benzothienyl includes benzothien-2-yl and benzothien-3-yl.
The term benzimidazolyl includes benzimidazol-2-yl.
The term benzoxazolyl includes benzoxazol-2-yl.
The term benzothiazolyl includes benzothiazol-2-yl.
The term indolyl includes indol-2-yl and indol-3-yl.
The term quinolyl includes quinol-2-yl.
In the compounds of formula I or formula XVII, preferably R2 and R3 each independently represents hydrogen or methyl. More preferably R2 represents methyl and R3 represents hydrogen.
R4 preferably represents ethyl, isopropyl or dimethylamino. More preferably R4 represents isopropyl.
In the compounds of formula I, R5 preferably represents hydrogen, hydroxy or together with R1 a bond.
In the compounds of formula I or formula XVII, R6 preferably represents cyclopentyl, or a furyl, thienyl, thiazolyl, pyridyl or phenyl group which is unsubstituted or substituted with one or two substituents selected independently from halogen; amino; cyano; formyl; carboxy; nitro; (1-4C)alkyl; (2-4C)alkenyl; (2-4C)alkynyl; halo(1-4C)alkyl; cyano(1-4C)alkyl; amino(1-4C)alkyl; (1-4C)alkyl-NHSO2R17; (1-4C)alkyl-CO2R18; (1-4C)alkyl-CO2H; (1-4C)alkyl-CONR9R10; (3-8C)cycloalkyl; 2,5-dimethylpyrrolyl; wherein R17 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; R18 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, and groups of formula (L1)x-X2-(L1)y-R11 in which each of L1 and L2 independently represents (1-4C)alkylene, one of x and y is 0 and the other is 0 or 1, X2 represents a bond, O, S, NH, CO, CONH or NHCO, and R11 represents a furyl, thienyl, thiazolyl, pyridyl or phenyl group which is unsubstituted or substituted by one or two of halogen, (1-4C)alkyl and (1-4C)haloalkyl.
More preferably, R6 represents 
in which R12, R13, R14, R15 and R16 represent halogen, amino, cyano, formyl, nitro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, halo(1-4C)alkyl, cyano(1-4C)alkyl, amino(1-4C)alkyl,; (1-4C)alkyl-NHSO2R17, (3-8C)cycloalkyl, wherein R17 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a group of formula (L1)x-X2-(L1)y-R11.
Most especially preferred, R6 represents: 
in which R12 R13 R14 R15 and R16 represent halogen, amino, cyano, formyl, nitro, (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, halo(1-4C)alkyl, cyano(1-4C)alkyl, amino(1-4C)alkyl; (1-4C)alkyl-NHSO2R17R (3-8C)cycloalkyl, wherein R17 represents (1-6C)alkyl, (3-6C)cycloalkyl, fluoro(1-6C)alkyl, chloro(1-6C)alkyl, (2-6C)alkenyl, (1-4C)alkoxy(1-4C)alkyl, phenyl which is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, (1-4C)alkylphenyl wherein the phenyl group is unsubstituted or substituted by halogen, (1-4C)alkyl or (1-4C)alkoxy, or NR9R10 in which each of R9 and R10 independently represents (1-4C)alkyl or together with the nitrogen atom to which they are attached form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, piperazinyl, hexahydroazepinyl or octahydroazocinyl group; or a group of formula (L1)x-X2-(L1)y-R11.
Examples of particular values for R6 are cyclopentyl, thien-2-yl, thien-3-yl, fur-3-yl, 5-(pyrid-2-yl)thien-2-yl, thiazol-2-yl, pyrid-2-yl, phenyl, 4-formylphenyl, 4-aminophenyl, 4-cyanophenyl, 4-cyanomethylphenyl, 4-aminomethylphenyl, 4-methylsulfonylaminoethylphenyl, 4-isopropylsulfonyl-aminomethylphenyl, or 4-(2,5-dimethylpyrrolyl)phenyl; or together with R5 and the carbon atom to which it is attached is spiroisobenzofuranyl.
In formula I, an example of a particular value for R7 is phenyl.
Preferably A represents CR5(X1R6).
According to another aspect, the present invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, which comprises:
(a) reacting a compound of formula 
xe2x80x83with a compound of formula
R4SO2Z1xe2x80x83xe2x80x83III
in which Z1 represents a leaving atom or group; or
(b) for a compound of formula I in which A represents CR5(X1R6), R5 represents hydroxyl and X1 represents a bond, reacting a compound of formula 
with a compound of formula
R6Z2xe2x80x83xe2x80x83V
in which Z2 represents an alkali or alkaline earth residue; or
(c) for a compound of formula I in which A represents Cxe2x95x90NO(CH2)nR7, reacting a compound of formula IV with a compound of formula
R7(CH2)nONH2xe2x80x83xe2x80x83VI
(d) for a compound of formula I in which A represents CR5(X1R6), and R5 together with R1 represents a bond, dehydrating a compound of formula 
(e) for a compound of formula I in which A represents CR5(X1R6), X1 represents a bond, and R5 together with R1 represents a bond, reacting a compound of formula 
xe2x80x83in which Z3 represents a leaving atom or group
xe2x80x83with a compound of formula
R6Mxe2x80x83xe2x80x83IX
in which M is B(OH)2, Br, I, or ZnY and Y is a halogen atom; or alternatively reacting a compound of formula VIII with a trialkyltin reagent;
(f) for a compound of formula I in which A represents CR5(X1R6), R1 represents hydrogen and R5 represents hydrogen, reducing a compound of formula VII;
(g) for a compound of formula I in which A represents CR5(X1R6), and X1 represents NHCO, reacting a compound of formula 
xe2x80x83with a compound of formula
R6COZ4xe2x80x83xe2x80x83XI
in which Z4 represents a leaving atom or group; followed, if desired, by forming a pharmaceutically acceptable salt.
In step (a) of the process according to the invention, the leaving atom or group represented by Z1 may be, for example, a halogen atom such as a chlorine or bromine atom.
The reaction is conveniently performed in the presence of a base, for example as alkali metal hydroxide such as sodium hydroxide, or a tertiary amine, such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. Suitable solvents include halogenated hydrocarbons, such as dichloromethane. The reaction is conveniently performed at a temperature in the range of from xe2x88x9220 to 100xc2x0 C., preferably from xe2x88x925 to 50xc2x0 C.
In step (b) of the process according to the invention, the alkali metal residue represented by Z2 may be, for example, lithium. The process is conveniently performed under an inert atmosphere and at a temperature in the range of from xe2x88x9278 to 25xc2x0 C. Suitable solvents include ethers, such as tetrahydrofuran or diethyl ether.
The compounds of formula IV may be prepared by hydrolyzing a ketal of formula 
in which each of Ra and Rb represents a (1-6C)alkyl group or together represent a (2-4C)alkylene chain. The hydrolysis is conveniently performed in the presence of hydrochloric acid at ambient temperature.
The compounds of formula XII may be prepared by reacting a compound of formula 
with a compound of formula III.
The reaction is conveniently performed according to the method of step (a) as described hereinabove.
The compounds of formula XIII may be prepared by reducing a nitrile of formula 
The reduction is conveniently performed using a hydride reducing agent such as lithium aluminum hydride. Suitable solvents include ethers such as diethyl ether or tetrahydrofuran.
Compounds of formula XIV in which R2 and R3 each represents hydrogen may be converted into compounds of formula XIV in which one or both of R2 and R2 represents (1-4C)alkyl by reaction with a (1-4C)alkyl halide in the presence of a strong base such as lithium bis(trimethylsilyl)amide. Convenient solvents include ethers, such as tetrahydrofuran.
The compounds of formula XIV in which R2 and R3 each represents hydrogen may be prepared by reacting a 1,4-cyclohexanedione monoketal, such as 1,4-cyclohexanedione monoethylene ketal, with a dialkyl (cyanomethyl)phosphonate, such as diethyl (cyanomethyl)phosphonate, in the presence of a strong base, such as sodium hydride, followed by reduction, for example by catalytic hydrogenation in the presence of palladium on carbon. Suitable solvents for the first step include ethers, such as tetrahydrofuran.
Suitable solvents for the reduction step include alcohols, such as ethanol.
Step (c) of the process according to the invention is conveniently performed at a temperature in the range of from xe2x88x9210 to 120xc2x0 C. Suitable solvents include halogenated hydrocarbons, such as dichloromethane.
The dehydration of a compound of formula VII according to step (d) of the process is conveniently performed by heating, for example to a temperature in the range of from 40 to 100xc2x0 C. Suitable solvents include halogenated hydrocarbons, such as dichloromethane.
In step (e) of the process according to the invention, the leaving atom or group represented by Z3 may be, for example, an organosulfonyloxy group, such as trifluoromethylsulfonyloxy or a trialkyltin, such as (Me)3Sn or (Bu)3Sn. The halogen atom represented by Y may be, for example, a bromine atom. The reaction is conveniently performed in the presence of a tetrakis(triarylphosphine)palladium halide catalyst, such as tetrakis(triphenylphosphine)palladium chloride, and a base, such as potassium carbonate. Convenient solvents for the reaction include ethers, such as dioxane or tetrahydrofuran. The temperature at which the reaction is conducted is preferably in the range of from 0 to 150xc2x0 C., preferably 75 to 120xc2x0 C.
The compounds of formula VIII in which Z3 represents an organosulfonyloxy group may be prepared by reacting a compound of formula IV with an N-arylsulfonimide, such as N-phenyltrifluoromethane sulfonimide. The reaction is conveniently performed in the presence of a strong base, such as lithium bis(trimethylsilyl)amide. Convenient solvents include ethers, such as tetrahydrofuran. The reaction is conveniently performed at from xe2x88x92100 to xe2x88x9250xc2x0 C.
The compounds of formula VII may be reduced according to step (f) of the process by reaction with a reducing agent, such as a trialkylsilane, for example triethylsilane, and boron trifluoride, conveniently as the diethyl etherate. The reaction is conveniently performed at a temperature of from xe2x88x92100 to xe2x88x9250xc2x0 C. Convenient solvents includes halogenated hydrocarbon, such as dichloromethane.
Alternatively, the compounds of formula VII may be reduced with a reducing agent such as borane dimethylsulfide complex. For example, compound VII is dissolved in a suitable organic solvent, such as tetrahydrofuran and heated to reflux. To the refluxing solution is added about 1.1 equivalents of borane dimethylsulfide via syringe. The mixture is heated at reflux for about 60 minutes and then cooled to room temperature. The reaction mixture is then treated with 6N HCl and then refluxed for about 60 minutes. The reaction mixture is again cooled to room temperature and the pH is adjusted to about pH 10 with 5N NaOH. The reaction mixture is then diluted with water and extracted with a suitable organic solvent, such as dichloromethane. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the reduced compound.
In process step (g), the leaving atom or group Z4 may be, for example, a halogen atom such as a chlorine atom. The reaction is conveniently performed in the presence of a base, for example a tertiary amine such as triethylamine, and at a temperature in the range of from 0 to 100xc2x0 C. Convenient solvents include halogenated hydrocarbons, such as dichloromethane.
The compounds of formula X may be prepared by reducing a compound of formula 
The reduction is conveniently performed using a hydride reducing agent, for example lithium aluminum hydride, and at a temperature of from 0 to 100xc2x0 C. Convenient solvents include ethers such as diethyl ether.
The compounds of formula II, used as starting materials in step (a), may be prepared by a process analogous to steps (b) to (g), but using a protected amino compound (for example, an N-acetyl compound) in place of a sulphonamide, and then removing the protecting group (for example by acid-catalyzed hydrolysis).
The compounds of formula XVII: 
may be prepared from compounds of formula XVI 
under conditions well known in the art. For example, a compound of formula XVI is dissolved in a suitable organic solvent, such as tetrahydrofuran, cooled to about 0xc2x0 C. and treated with a suitable borane reducing agent, such as borane dimethyl sulfide complex. The reaction mixture is stirred for about 4 hours at 0xc2x0 C. and then slowly quenched with ethanol. The solution is maintained at about 0xc2x0 C. and 3N aqueous sodium hydroxide is added followed by 30% hydrogen peroxide. The reaction mixture is then stirred for about one hour at 0xc2x0 C. The compound of formula XVII is then isolated and purified by techniques well know in the art such as extraction techniques and flash chromatography. For example, the organic layer is separated and the aqueous layer is extracted with a suitable organic solvent, such as diethyl ether. The organic layer and extracts are then combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The crude material can then be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide purified XVII.
More specifically, compounds of formulas XIX and XX can be prepared as shown in Scheme I. Reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified, are previously defined. 
In Scheme I, step A the compound of formula XVIII wherein Q represents a (3-8C)cycloalkyl, an aromatic group, unsubstituted or substituted, such as phenyl, or a heteroaromatic group, unsubstituted or substituted, and Rp represents hydrogen, hydroxy, or together with R5 a bond, q is an integer 1, 2, 3 or 4, and the remaining substituents are defined as hereinabove, is converted to the amine of formula XIX under conditions well known in the art. For example, compound XVIII is dissolved in a suitable organic solvent, such as tetrahydrofuran and heat to reflux. To the refluxing solution is added about 1.1 equivalents of a borane reagent, such as borane dimethylsulfide complex. The reaction mixture is then heated at reflux for about 1 to 2 hours, cooled to room temperature and then treated with 6N HCl. The reaction is again heated at reflux for about 1 hour, cooled and the pH is adjusted to about pH 10 with aqueous sodium hydroxide. The product, compound XIX, is then isolated and purified by standard techniques such as extraction and chromatography.
For example, the reaction mixture is diluted with water and extracted with a suitable organic solvent, such as dichloromethane. The organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide compound XIX.
In Scheme I, step B compound XIX is sulfonylated to provide the compound of formula XX under conditions well known in the art. For example, compound XIX is dissolved in a suitable organic solvent, such as dichloromethane, followed by addition of about 1.05 equivalents of triethylamine. The solution is cooled to about 0xc2x0 C. and treated with about 1.05 equivalents of a suitable sulfonyl chloride of formula R17SO2Cl, such as methanesulfonyl chloride. The reaction is then allowed to warm to room temperature over 2 hours with stirring. The product, compound XX, is then isolated and purified using techniques well known to one of ordinary skill in the art, such as extraction and chromatography.
For example, the reaction mixture is then diluted with a suitable organic solvent, such as dichloromethane and 10% aqueous sodium bisulfate. The organic layer is separated and the aqueous layer is extracted with dichloromethane.
The organic layer and extracts are then combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide compound XX. Compound XX can then be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide purified compound XX.
Compounds of formulas XXI and XXII can be prepared as disclosed in Scheme II. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified, are previously defined. 
In Scheme II, step A the compound of formula XVIII can be hydrolyzed under standard conditions to provide the compound of formula XXI. For example, compound XVIII is dissolved in a suitable organic solvent, such as dioxane and treated with a suitable base, such as sodium hydroxide. The reaction mixture is then heated at about 100xc2x0 C. for about 24 hours. The reaction mixture is then cooled to room temperature and acidified with 10% sodium bisulfate. Compound XXI is then isolated and purified by techniques well known in the art, such as extraction and chromatography.
For example, the reaction mixture is extracted with a suitable organic solvent, such as ethyl acetate, the organic extracts are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide compound XXI. Compound XXI can be purified by flash chromatography on silica gel with a suitable eluent, such as methanol/chloroform.
In Scheme II, step B the compound of formula XXI can be esterified under conditions well known in the art to provide the compound of formula XXII. For example, compound XXI is dissolved in a suitable alcoholic organic solvent of formula R18OH, such as ethanol and HCl gas is bubbled through the solution until the mixture is saturated. The reaction mixture is then heated at 60xc2x0 C. for about 24 hours, then cooled to room temperature and concentrated under vacuum. Additional ethanol is added to the residue and the mixture is again concentrated under vacuum to provide the ethyl ester of compound XXII. Compound XXII can be then be purified by flash chromatography on silica gel with a suitable eluent, such ethyl acetate/hexane.
Compounds of formula XXIII can be prepared as disclosed in Scheme III. Starting material and reagents are readily available to one ordinary skill in the art. All substituents, unless otherwise specified, are previously defined. 
In Scheme III, step A compound XXI is readily converted to the amide of formula XXIII under conditions well known in the art. For example, compound XXI is dissolved in a suitable organic solvent, such as tetrahydrofuran and treated with an excess of thionyl chloride. The reaction mixture is stirred at room temperature for about 16 hours and then concentrated under vacuum. The residue is then dissolved in a suitable organic solvent, such as methylene chloride. The solution is added to a solution of one equivalent of a suitable amine of formula R9R10NH, such as dimethylamine in dichloromethane with stirring. The mixture is stirred for about 2 hours at about 0xc2x0 C. and then 10% aqueous sodium bisulfate is added. Compound XXIII is then isolated and purified by techniques well known in the art, such as extraction and flash chromatography.
For example, the reaction mixture is then extracted with a suitable organic solvent, such as methylene chloride, the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide compound XXIII. This can then be purified by flash chromatography on silica gel with a suitable eluent, such as ethyl acetate/hexane to provide the purified compound XXIII.
Some of the intermediates disclosed herein, for example the compounds of formula IV, are novel and are provided as further aspects of the invention.
The ability of compounds of formula I or formula XVII to potentiate glutamate receptor-mediated response may be determined using fluorescent calcium indicator dyes (Molecular Probes, Eugene, Oreg., Fluo-3) and by measuring glutamate-evoked efflux of calcium into GluR4 transfected HEK293 cells, as described in more detail below.
In one test, 96 well plates containing confluent monolayers of HEK cells stably expressing human GluR4B (obtained as described in European Patent Application Publication Number EP-A1-583917) are prepared. The tissue culture medium in the wells is then discarded, and the wells are each washed once with 200 xcexcl of buffer (glucose, 10 mM, sodium chloride, 138 mM, magnesium chloride, 1 mM, potassium chloride, 5 mM, calcium chloride, 5 mM, N-[2-hydroxyethyl]piperazine-N-[2-ethanesulfonic acid], 10 mM, to pH 7.1 to 7.3). The plates are then incubated for 60 minutes in the dark with 20 xcexcM Fluo3-AM dye (obtained from Molecular Probes Inc., Eugene, Oreg.) in buffer in each well. After the incubation, each well is washed once with 100 xcexcl buffer, 200 xcexcl of buffer is added and the plates are incubated for 30 minutes.
Solutions for use in the test are also prepared as follows. 30 xcexcM, 10 xcexcM, 3 xcexcM and 1 xcexcM dilutions of test compound are prepared using buffer from a 10 mM solution of test compound in DMSO. 100 xcexcM cyclothiazide solution is prepared by adding 3 xcexcl of 100 mM cyclothiazide to 3 ml of buffer. Control buffer solution is prepared by adding 1.5 xcexcl DMSO to 498.5 xcexcl of buffer.
Each test is then performed as follows. 200 xcexcl of control buffer in each well is discarded and replaced with 45 xcexcl of control buffer solution. A baseline fluorescent measurement is taken using a FLUOROSKAN II fluorimeter (Obtained from Labsystems, Needham Heights, Mass., USA, a Division of Life Sciences International Plc). The buffer is then removed and replaced with 45 xcexcl of buffer and 45 xcexcl of test compound in buffer in appropriate wells. A second fluorescent reading is taken after 5 minutes incubation. 15 xcexcl of 400 xcexcM glutamate solution is then added to each well (final glutamate concentration 100 xcexcM), and a third reading is taken. The activities of test compounds and cyclothiazide solutions are determined by subtracting the second from the third reading (fluorescence due to addition of glutamate in the presence or absence of test compound or cyclothiazide) and are expressed relative to enhance fluorescence produced by 100 xcexcM cyclothiazide.
In another test, HEK293 cells stably expressing human GluR4 (obtained as described in European Patent Application Publication No. EP-A1-0583917) are used in the electro-physiological characterization of AMPA receptor potentiators. The extracellular recording solution contains (in mM): 140 NaCl, 5 KCl, 10 HEPES, 1 MgCl2, 2 CaCl2, 10 glucose, pH=7.4 with NaOH, 295 mOsm kg-1. The intracellular recording solution contains (in mM): 140 CsCl, 1 MgCl2, 10 HEPES, (N-[2-hydroxyethyl]piperazine-N1-[2-ethanesulfonic acid]) 10 EGTA (ethylene-bis(oxyethylene-nitrilo)tetraacetic acid), pH=7.2 with CsOH, 295 mOsm kg-1. With these solutions, recording pipettes have a resistance of 2-3 Mxcexa9. Using the whole-cell voltage clamp technique (Hamill et al. (1981)Pflxc3xcgers Arch., 391: 85-100), cells are voltage-clamped at xe2x88x9260mV and control current responses to 1 mM glutamate are evoked. Responses to 1 mM glutamate are then determined in the presence of test compound. Compounds are deemed active in this test if, at a test concentration of 10 xcexcM, they produce a greater than 30% increase in the value of the current evoked by 1 mM glutamate.
In order to determine the potency of test compounds, the concentration of the test compound, both in the bathing solution and co-applied with glutamate, is increased in half log units until the maximum effect was seen. Data collected in this manner are fit to the Hill equation, yielding an EC50 value, indicative of the potency of the test compound. Reversibility of test compound activity is determined by assessing control glutamate 1 mM responses. Once the control responses to the glutamate challenge are re-established, the potentiation of these responses by 100 xcexcM cyclothiazide is determined by its inclusion in both the bathing solution and the glutamate-containing solution. In this manner, the efficacy of the test compound relative to that of cyclothiazide can be determined.
According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula I or formula XVII or a pharmaceutically acceptable salt thereof as defined hereinabove and a pharmaceutically acceptable diluent or carrier.
As used herein the term xe2x80x9cmammalxe2x80x9d refers to a mouse, guinea pig, rat, dog, human and the like. It is understood that the preferred mammal is a human.
As used herein the term xe2x80x9ceffective amountxe2x80x9d refers to the amount or dose of the compound which provides the desired effect in the mammal under diagnosis or treatment.
The pharmaceutical compositions are prepared by known procedures using well-known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
The particular dose of compound administered according to this invention will of course be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations. The compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.